Hepatitis C virus (HCV) is the major etiological agent of 90% of all cases of non-A, non-B hepatitis (Choo et al., 1989, Kuo et al., 1989). The incidence of HCV infection is becoming an increasingly severe public health concern with 2-15% individuals infected worldwide. While primary infection with HCV is often asymptomatic, most HCV infections progress to a chronic state that can persist for decades. Of those with chronic HCV infections, it is believed that about 20-50% will eventually develop chronic liver disease (e.g. cirrhosis) and 20-30% of these cases will lead to liver failure or liver cancer. As the current HCV-infected population ages, the morbidity and mortality associated with HCV are expected to triple.
An approved treatment for HCV infection uses interferon (IFN) which indirectly effects HCV infection by stimulating the host antiviral response. IFN treatment is largely ineffective, however, as a sustained antiviral response is produced in less than 30% of treated patients. Further, IFN treatment induces an array of side effects of varying severity in upwards of 90% of patients (eg: acute pancreatitis, depression, retinopathy, thyroiditis). Therapy with a combination of IFN and ribavirin has provided a slightly higher sustained response rate, but has not alleviated the IFN-induced side effects.
A general strategy for the development of antiviral agents has been to inactivate virally encoded enzymes essential for viral replication. In the case of HCV, an inhibitor selectively targeting the HCV serine protease, NS3, would likely provide an advantageous therapy for treating HCV infections in patients by inhibiting HCV replication.
Amongst the compounds that have demonstrated efficacy in inhibiting HCV replication, as selective HCV NS3 serine protease inhibitors, are the tri-peptide compounds disclosed in International Application Number PCT/CA99/00736, Publication No. WO 00/09543, titled Hepatitis C Inhibitor Tri-Peptides. However, these compounds do not sufficiently inhibit HCV serine protease or do not have sufficient potency, and thus, may not provide optimal treatment of HCV-infected patients.
What is needed are compounds, useful for treating HCV-infected patients, by selectively inhibiting HCV NS3 serine protease, wherein these compounds have a suitable cell permeability to sufficiently inhibit HCV replication within the patient's body.